TY - JOUR AB - In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity. AD - Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland Wroclaw Research Centre EIT+, 54-066 Wroclaw, Poland Pharmaceutical Research Institute, 01-793 Warsaw, Poland AU - Milczarek,Magdalena AU - Filip-Psurska,Beata AU - Świętnicki,Wiesław AU - Kutner,Andrzej AU - Wietrzyk,Joanna DA - 2014/08/01 DO - 10.3892/or.2014.3247 EP - 504 IS - 2 JO - Oncol Rep KW - vitamin D analogs colon cancer combined treatment 5-fluorouracil PY - 2014 SN - 1021-335X 1791-2431 SP - 491 ST - Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment T2 - Oncology Reports TI - Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment UR - https://doi.org/10.3892/or.2014.3247 VL - 32 ER -